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- Title
Dopaminergic neurons of system x<sub>c</sub><sup>-</sup>-deficient mice are highly protected against 6-hydroxydopamine-induced toxicity.
- Authors
Massie, Ann; Schallier, Anneleen; Seong Woong Kim; Fernando, Ruani; Kobayashi, Sho; Beck, Heike; De Bundel, Dimitri; Vermoesen, Katia; Bannai, Shiro; Smolders, Ilse; Conrad, Marcus; Plesnila, Nikolaus; Sato, Hideyo; Michotte, Yvette
- Abstract
Malfunctioning of system xc- , responsible for exchanging intracellular glutamate for extracellular cystine, can cause oxidative stress and excitotoxicity, both important phenomena in the pathogenesis of Parkinson's disease (PD). We used mice lacking xCT (xCT-/- mice), the specific subunit of systemxc-, to investigate the involvement of this antiporter in PD. Although cystine that is imported via system xc- is reduced to cysteine, the rate-limiting substrate in the synthesis of glutathione, deletion of xCT-/- did not result in decreased glutathione levels in striatum. Accordingly, no signs of increased oxidative stress could be observed in striatum or substantia nigra of xCT-/- mice. In sharp contrast to expectations, xCT-/- mice were less susceptible to 6-hydroxydopamine (6-OHDA)-induced neurodegeneration in the substantia nigra pars compacta compared to their age-matched wild-type littermates. This reduced sensitivity to a PD-inducing toxin might be related to the decrease of 70% in striatal extracellular glutamate levels that was observed in mice lacking xCT. The current data point toward system xc- as a possible target for the development of new pharmacotherapies for the treatment of PD and emphasize the need to continue the search for specific ligands for system xc-.
- Subjects
DOPAMINERGIC mechanisms; GLUTAMIC acid; OXIDATIVE stress; GLUTATHIONE; LABORATORY mice; LIGANDS (Biochemistry); NEURONS
- Publication
FASEB Journal, 2011, Vol 25, Issue 4, p1359
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.10-177212